Biomarker studies for immunotherapies have typically involved monitoring immunologic changes within the systemic circulation; however, recent data indicates that immunological changes within tumor tissues are more likely to predict clinical responses. We conducted a pre-surgical clinical trial with anti-CTLA-4 (ipilimumab) in patients with localized bladder cancer, and identified ICOS as the marker of a subset of effector T cells that is increased in frequency after anti-CTLA-4 therapy. ICOS+ T cells are being explored as pharmacodynamic markers for treatment with anti-CTLA-4 and as novel targets to improve the efficacy of anti-CTLA-4 therapy.

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With the number of cancer cases plummeting every year, there is a dire need for finding a cure to wipe the disease out. A number of therapeutic drugs are currently in use, however, due to heterogeneity of the disease targeted therapy is required. An important criteria that needs to be addressed in this context is the –‘tumor response’ and how it could be predicted, thereby improving the selection of patients for cancer treatment. The issue of tumor response has been addressed in a recent editorial titled “Tumor response criteria: are they appropriate?” published recently in Future Oncology.

The article talks about how the early tumor treatment response methods came into practice and how we need to redefine and reassess the tumor response.

Defining ‘tumor response’ has always been a challenge

WHO defines a response to anticancer therapy as 50% or more reduction in the tumor size measured in two perpendicular diameters. It is based on the results of experiments performed by Moertel and Hanley in 1976 and later published by Miller et al in 1981. Twenty years later, in the year 2000, the US National Cancer Institute, with the European Association for Research and Treatment of Cancer, proposed ‘new response criteria’ for solid tumors; a replacement of 2D measurement with measurement of one dimen­sion was made. Tumor response was defined as a decrease in the largest tumor diameter by 30%, which would translate into a 50% decrease for a spherical lesion. However, response criteria have not been updated after that and there a structured standardization of treatment response is still required especially when several studies have revealed that the response of tumors to a therapy via imaging results from conventional approaches such as endoscopy, CT scan, is not reliable. The reason is that evaluating the size of tumor is just one part of the story and to get the complete picture inves­tigating and evaluating the tissue is essential to differentiate between treatment-related scar, fibrosis or micro­scopic residual tumor.

In clinical practice, treatment response is determined on the basis of well-established parameters obtained from diagnostic imaging, both cross-sectional and functional. In general, the response is classified as:

For a doctor examining the morphology of the tumor, complete remission might seem like good news, however, mission might not be complete yet! For example, in some cases, with regard to prognosis, patients with 0% residual tumor (complete tumor response) had the same prognosis com­pared with those patients with 1–10% residual tumor (subtotal response).

Another example is that in patients demonstrating complete remission of tumor response as observed with clinical, sonographic, functional (PET) and histopathological analysis experience recur­rence within the first 2 years of resection.

Adding complexity to the situation is the fact that the appropriate, clinically relevant timing of assess­ment of tumor response to treatment remains undefined. An example mentioned in the editorial is – for gastrointestinal (GI) malignancies, the assessment timing varies considerably from 3 to 6 weeks after initia­tion of neoadjuvant external beam radiation. Further, time could vary depending upon the type of radiation administered, i.e., if it is external beam, accelerated hyperfractionation, or brachytherapy.

Abovementioned examples remind us of the intricacy and enigma of tumor biol­ogy and subsequent tumor response.

Conclusion

Owing to the extraordinary het­erogeneity of cancers between patients, and pri­mary and metastatic tumors in the same patients, it is important to consider several factors while determining the response of tumors to different therapie in clinical trials. Authors exclaim, “We must change the tools we use to assess tumor response. The new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ charac­teristics.”

Future perspective

Editorial points out that the oncologists, radiotherapists, and immunologists all might have a different opinion and observation as far as tumor response is considered. For example, surgical oncologists might determine a treatment to be effective if the local tumor control is much better after multimodal treatment, and that patients post-therapeutically also reveal an increase of the rate of microscopic and macroscopic R0-resection. Immunologists, on the other hand, might just declare a response if immune-competent cells have been decreased and, possibly, without clinical signs of decrease of tumor size.

What might be the answer to the complexity to reading tumor response is stated in the editorial – “an interdisciplinary initiative with all key stake­holders and disciplines represented is imperative to make predictive and prognostic individualized tumor response assessment a modern-day reality. The integrated multidisciplinary panel of international experts need to define how to leverage existing data, tissue and testing platforms in order to predict individual patient treatment response and prog­nosis.”